A Phase 1 Dose-Escalation Study of Robotic Radiosurgery in Inoperable Primary Renal Cell Carcinoma

Abstract

Extreme hypofractionated radiation therapy has been shown to be effective in controlling metastatic disease in traditionally radioresistant tumors. We sought to evaluate the toxicity of hypofractionated radiation therapy in the treatment of medically inoperable, primary renal cell carcinoma. From November 2006 to December 2010, we enrolled 15 patients with medically inoperable Stage IA/B renal cell carcinoma (RCC) on a Phase I dose escalation study. Patients were eligible who had either biopsy-confirmed RCC or radiographic findings of sufficient concern to otherwise warrant partial or radical nephrectomy; primary lesions had to be ≤ 5cm and patients had to have KPS ≥ 70. Patients with tumors near the collecting system or large vessels were included. We examined five potential dose arms: 7 Gy x 3, 9 Gy x 3, 11 Gy x 3, 13 Gy x 3, and 16 Gy x 3. Dose-Limiting Toxicities (DLT) were defined as any non-hematologic grade 3-4 toxicity within 90 days of treatment. Treatment was delivered using the robotic radiosurgical device. Patients were followed every 6 months for a minimum of 2 years. Acute and late toxicities were examined using CTCAE v 3.0 and RTOG classifications, respectively. Serial creatinine, eGFR, and differential renal function (via renal scintigraphy scans) were obtained at each follow-up. Local tumor control was defined using RECIST criteria. Median age was 75 years (range, 45-90); mean maximal tumor dimension was 3.4 cm; nine (60%) of patients had baseline chronic kidney disease (CKD). Median follow-up was 36.7 months (range, 24.2-72.2). There were no DLTs; we were able to escalate through all dose arms (3 patients per arm). Two patients had acute grade 1 nausea, and five had acute grade 1 fatigue. One patient had late grade 3 renal dysfunction. At 24 months, compared to baseline, there was a significant decline in both mean eGFR (from 55 mg/dL to 37 mg/dL, p = 0.002) and differential renal function as assayed by renal scintigraphy (from −2.75 to −17.13, p = 0.01). At 12 months, 11 patients had stable disease, 2 had partial response, 1 had complete response, and 1 had progressive disease. Ultimately, there were two local failures at 30.7 months and 31.2 months. Both were in low dose arms (7 Gy x 3 and 9 Gy x 3), and one patient was successfully salvaged with repeat treatment. With minimum follow-up of 2 years, extreme hypofractionation for primary renal cell carcinoma is safe, with minimal acute toxicities; decrements in renal function in a population with significant baseline chronic kidney disease were equivalent to historical series of partial nephrectomy. No toxicity was observed treating tumors near the collecting system or major vascular structures. Future studies may want to use, at a minimum, 16 Gy x 3.